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In this chapter, the history of biotechnology from original fermentation to genetic engineering is introduced concisely. New expressions from chemical biology to chemically promoted biotechnology and bioengineering are introduced. The focus is on the applications of chemistry to biotechnology, which is directly simplified as “chemical biotechnology”. Some examples of chemically promoted biotechnologies are taken to illustrate this concept, such as: modulators in enzymatic reactions; small molecules and carbon materials in the regulation of non-canonical DNA structures; chemically promoted biomimetic cofactors in in vitro biosystems for the production of high-value chemicals and low-value biocommodities; some chemicals used in microbial electrochemical systems (MES) to improve the performance/efficiency of extracellular electron transfer between the bacteria and the electrode; elicitors in plant cell culture; and plant activators in crop protection.

The term ‘biotechnology’ first appeared in Manchester University, England, early in the 20th century.1  In 1912, C. Weizmann isolated a strain of Clostridium acetobutylicum that converted carbohydrate into butanol, acetone, and ethanol.2  In 1923, T. Walker commenced undergraduate education in the department of fermentation industries; the name of this department was then changed to industrial biochemistry, similar to ‘biotechnology’.1  K. Ereky, a Hungarian engineer and the founding father of biotechnology,3  first coined the word “biotechnology” in a book published in Berlin in 1919 called Biotechnologie der Fleisch-, Fett- und Milcherzeugung im landwirtschaftlichen Grossbetriebe (Biotechnology of Meat, Fat and Milk Production in an Agricultural Large-Scale Farm), in which he explained a bioprocess technology that converts raw materials into a more valuable product. He further developed this concept for the 20th century: Biotechnology means solutions to many social and natural crises, such as food and energy shortages.2 

In fact, biotechnology as a methodology has existed for a long time, although the term “biotechnology” did not exist then. Around 8000 BC yeast was used to make wheat wine by the Chinese, and also around 6000 BC by the Sumerians and Babylonians.4  Around 4000 BC the Egyptians used yeast to bake leavened bread. The ancient Chinese produced copious amounts of liquor, rice wine, soy sauce, and vinegar with the earliest biotechnology utilizing conversion by some microbes.5 

In AD 1673 A. v. Leeuwenhoek, a Dutch scientist known as “the father of microbiology”, pointed out the functions of microorganisms in fermentation6  and made contributions towards handcrafted microscopes and the establishment of microbiology. He was the first one to observe and describe single-celled organisms as animalcules, which are now referred to as microorganisms.

Vaccines, which protect people from some terrible diseases, are a typical biotechnology.7  In the 16th century, the Chinese inoculated smallpox scab powder on the body to protect from smallpox infection. E. Jenner (1749–1823), an English physician known as “the father of immunology”, heard a dairymaid’s story and started to study cowpox vaccine. L. Pasteur (1822–1895), the other founder of medical microbiology, was famous for his creation of two vaccines for rabies and anthrax.

A. Fleming (1881–1955), a Scottish scientist, discovered the antibiotic penicillin, a secondary metabolite from Penicillium fungi, in 1928,8  the most famous example of a biopharmaceutical from biotechnology. Now, the majority of penicillin employed worldwide is produced by this kind of method in China.

Today’s biotechnology in the form of genetic engineering was established by G. Mendel (1822–1884), an Austrian scientist and the father of modern genetics.9  W. Sutton (1877–1916), an American scientist, applied the Mendelian laws of inheritance to the cellular level of living organisms and established chromosome theory.10  The structure of DNA was discovered by J. Watson (born April 6, 1928), an American scientist, with F. Crick (1916–2004), an English scientist, in 1953. This discovery resulted in an explosion of research in molecular biology and genetics, opening the door for the biotechnology revolution.11 

P. Berg (born June 30, 1926), an American scientist awarded the Nobel Prize in Chemistry in 1980, obtained the first recombinant DNA molecule and established the foundation for modern biotechnology.12 

Biochemistry is a traditional discipline focused on the knowledge and principles of the behavior of natural and endogenous chemicals or substances in life and biological systems. However, chemical biology is a young scientific discipline spanning chemistry, biology, and physics; it mainly uses chemistry, i.e. exogenous (or exogenously added) chemicals as a perturbation methodology to reveal biological laws or solve biological problems. It involves the application of chemical techniques, tools, and analyses, and chemicals from nature or produced through synthetic chemistry, for the study and manipulation of biological systems.

Science is the foundation of technology and engineering. Technology and engineering are the derivation and application of science, which really solve the practical problems related with social and natural crises. Accordingly, chemistry has chemical technology and engineering as its partner, and biochemistry has biochemical technology and engineering as its partner, so chemical biology should have its own partner—chemical biotechnology and bioengineering!

However, new methodology is needed to solve many practical problems. We know that biochemical technology or engineering can be defined as using biological methodologies and substances to solve practical and chemical problems in the areas of industry, medicine, and agriculture. Therefore, chemical biotechnology or bioengineering can be defined as using chemical methodologies and substances to solve practical and biological problems. Although one or two publications have used “chemical biotechnology or bioengineering” to describe some processes in the former case for solving chemical problems in the chemical industry, in fact these are still biochemical technology or engineering, not real chemical biotechnology or bioengineering for the processes in the latter case.

If some exogenous (or exogenously added) chemical compounds are able to regulate (enhance or attenuate) a bioprocess for some desired objectives, we believe that the whole process belongs to the area of “chemical biology” or “chemical biotechnology”. However, there are some differences between chemical biology and chemical biotechnology or bioengineering. The former focuses on the theory, mechanisms, and activities in the laboratory, and the latter focuses on the operation value in the laboratory and applications in practice even beyond the laboratory.

Today, there is a distinct definition: Biotechnologies are processes that seek to transform biological materials of animal, vegetable, microbial, or viral origin into products of commercial, economic, social, and/or hygienic utility and value, and bioengineering focuses on their scale up methodology.

Therefore, the definition of chemical biotechnology and bioengineering is utilizing small chemical molecules to affect some specific bioprocesses in order to make this bioprocess perform better, or on a larger scale for improving our lives and the health of our planet, which could transfer some ecological biotechnologies more economically and make the relevant chemistry greener (Figure 1.1).

Figure 1.1

Illustration of chemical biotechnology and bioengineering.

Figure 1.1

Illustration of chemical biotechnology and bioengineering.

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In fact, for the latter these processes could be recognized as a type of green chemistry approach when used to solve chemical problems. For example, enzymatic reactions to achieve exquisite chemo-, regio-, and enantio-selectivities for pharmaceuticals with great sustainability in aqueous media and under mild conditions as described in Chapter 2, or multi-enzyme-based biotransformations to produce chiral compounds as drug precursors, sweet hydrogen, sugar biobatteries, and renewable chemicals under green conditions, as exemplified in Chapter 3.

Sustainability has become a central and focal issue for human beings today, even a political issue, but it previously did not attract much attention in human history. Strong disputes and conflicts as well as many stories at The World Climate Congress every year fully embody the world’s anxiety on this problem. With conflicts between development and the environment, it seems to be impossible to reach a harmonious balance between GDP (Gross Domestic Product) and GWP (Global Warming Potential). In this situation and stage, green chemistry is a new and acceptable solution or option that has been proposed to solve the balance between the economy and ecology.

Green chemistry embodies two main aspects. First, it emphasizes the efficient utilization of raw or natural materials and the concomitant elimination of waste. Second, it deals with the health, safety, and environmental issues associated with the manufacture, use, and disposal or re-use of chemicals.

Green chemistry as an important concept first appeared in the early 1990s, about 20 years ago. Since then, it has made great progress in many areas, including petrochemicals, pharmaceuticals, household products, agriculture, aerospace, automobiles, cosmetics, electronics, and energy. There are hundreds and thousands of examples of successful applications of award winning, cost-effective, or economically competitive technologies. Many of them have played a significant role in informing sustainable design.13  Important early stories include the US Presidential Green Chemistry Challenge Awards established in 1995 and the publication of the first volume of Green Chemistry, a journal from the Royal Society of Chemistry, in 1999.14 

Green chemistry is a very important issue to scientists, engineers and society, and biotechnology is an efficient and attractive route to make chemicals and manufacturing processes cleaner or greener, efficiently and ecologically. However, from the economical view, most natural bioprocesses are still not robust enough for practical applications and industry; some chemical inducing agents, e.g. elicitors, modulators, and activators, are needed to promote or enhance the efficiencies of these biotechnologies, therefore, chemically promoted biotechnology and bioengineering make sense in this area.

In many cases, from the perspective of chemistry, it is difficult to understand the results of enzymatic reactions. For example, it seems strange that only one enantiomer in a racemic compound reacts in an enzymatic reaction if we do not understand the specific interactions between the enzyme and the substrate at the molecular level. The special compositions and structures of biomacromolecules endow enzymes with special functions. A typical, well-modulated biotransformation is usually considered to be a green process. It is estimated that biocatalysis technologies will decrease consumption of raw materials, water resources, and energy, and reduce waste emissions by 30% in 2020.15 

Most enzymatic reactions are performed under mild conditions, such as in water, at room temperature, and at atmospheric pressure, leading to lower energy consumption and operational risks. In addition, it is widely known that enzymes are capable of catalyzing highly regio-, chemo-, and enantio-selective reactions without performing the lengthy chemical protection/deprotection steps required in traditional chemical synthesis.

In spite of the superiority mentioned above, biotransformations are usually not satisfactory in industry without being carefully modulated. One dominant advantage, and sometimes also a drawback, encountered in biotransformations is that enzymatic reactions are traditionally performed in aqueous environments. However, the majority of organic chemicals are water-immiscible, resulting in very low substrate loading and low volumetric productivity.

In order to enhance the efficiency of biotransformations, chemical modulation can be used, on a case by case basis, to tune the enzyme activity, selectivity, and stability under specific reaction conditions.16  General methods could be used to improve reaction efficiency, for example, the selection of solvent systems, buffer salts, certain metal ions, and pH adjustments have been reported to work well. The structures and properties of enzymes can be readily regulated in the presence of small-molecule modulators. For example, it is well known that enzymes are able to coordinate with metal ions, which leads to some changes in their properties. In this context, the design and application of chemical modulators in enzymatic reactions is a typical example of chemical biotechnology, as detailed in Chapter 2.

The regular double-helix structure of DNA, typically B-DNA, in which two complementary strands are held together by Watson–Crick base pairs, is well recognized. Recently it has been found that under certain conditions DNA can form non-canonical structures, such as Z-DNA, A-motif, tetraplex, triplex, hairpin, and cruciform. These structures are particularly seen in the human genome with repeat DNA sequences, and some of them have been proposed to participate in several biologically important processes, including gene regulation, expression, and evolution, and thus could be potential drug targets.

The structures and properties of these non-canonical DNA are closely related to their biological functions. Due to their unique three-dimensional structures, small molecules can bind to them to stabilize or alter their structures, and are eventually able to regulate their biological functions. One of the most successful such small molecules is cis-diamminedichloroplatinum(ii), or cisplatin, a commonly used anti-cancer drug. It can covalently bind to DNA molecules, forming a DNA–cisplatin adduct that eventually inhibits DNA synthesis. Therefore, exploring the small molecules that can interact with DNA, especially with non-canonical DNA molecules, is an effective route to anti-cancer drug discovery.

In addition to small molecules, carbon materials such as carbon nanotubes (CNTs) and graphene oxides (GO) also exhibit the ability to tune the structure of typical helical DNA and non-canonical DNA structures due to their unique structural, chemical, and physical properties. Thus, their interactions with DNA attract tremendous research interest from scientists from different fields. Particular focus will be given to the applications of CNTs and GO in gene delivery and anti-cancer drugs in Chapter 3.

The use of single enzymes has been commercialized for more than a half century for the production of fructose, chemicals, and semi-synthetic antibiotics. The use of cell extracts for the production of high-value vaccines, vitamins, and proteins has been studied for the last two decades. Whole cells, especially microbes, have been utilized in the production of fermented food, beer, wines, drugs, chemicals, and so forth, to meet mankind’s myriad needs for thousands of years.

In vitro biosystems, also called synthetic pathway biotransformations, synthetic chemistry methodology approaches, enzyme cocktails, synthetic cascade enzyme factories, synthetic cascade manufacturing, synthetic biochemistry, and so on, are the in vitro assembly of a number of enzymes, which may be isolated from different organisms, and/or natural or biomimetic coenzymes, for the production of desired products that may not be produced by microbes or abiotic catalysts.17  For example, non-food cellulose can be converted to synthetic starch catalyzed by cascade enzymes in an aqueous solution requiring neither energy input nor chemical consumption.

In vitro biosystems for biomanufacturing feature several industrial production advantages over whole-cell-based biomanufacturing. High product yield is accomplished by the elimination of side reactions and no synthesis of cell mass; fast volumetric productivity can be achieved due to the better mass transfer without the barrier of cell membranes; easy product separation can be achieved without cell membranes; enzymes usually tolerate toxins and solvents much better than whole cells because of a lack of labile cell membranes; the reconstitution of synthetic enzymatic pathways can implement some non-natural reactions that could never occur in living cells; the reaction equilibrium may be shifted in favor of the product formation through well-designed synthetic enzymatic pathways.18 

In this system, a cofactor is a non-protein chemical compound that is required for the enzyme’s biological activity. It can be considered as a “helper molecule” that assists the biochemical transformations, which we can regard as one kind of chemical biotechnology.

Organic cofactors include nicotinamide adenine dinucleotide phosphate (NADP), nicotinamide adenine dinucleotide (NAD), flavin adenine dinucleotide (FAD), adenosine triphosphate (ATP), quinone compounds, and coenzyme A (CoA). Some organic cofactors are not stable enough for long-time bioprocessing. The most promising solution is the replacement of organic cofactors with low-cost and stable biomimetic ones. Such biomimetic cofactors that share a similar structure and function with their naturally occurring counterparts can be chemically synthesized at low costs and have enhanced stability.

Electrochemical systems catalyzed with whole-cell microorganisms, which are termed as microbial electrochemical systems (MES), including microbial fuel cells (MFC), microbial electrolysis cells (MEC), and microbial electrosynthesis cells (MESy), provide fascinating solutions for the sustainable development of the earth. They have been demonstrated to be promising for wastewater treatment, bioenergy harvesting, CO2 fixation and biotransformation, etc., but low power output due to low efficiency of electron releasing, extracellular electron transfer, and cell–electrode interactions largely limits the practical applications of MES. Therefore, multidisciplinary efforts have been made to improve the performance of MES. Most impressively, chemical bioengineering, referring to the use of chemical strategies to manipulate biological processes, has contributed largely to the recent advances in MES technology.

In particular, redox chemicals (serving as electron shuttles) naturally synthesized by bacteria or exogenously added synthetic molecules have been proved to be directly involved in promoting extracellular electron transfer between the cells and the electrode. Moreover, electrode modification with conductive polymers or carbon nanomaterials showed great potential for the enhancement of nanoscale topological interactions and hence the extracellular electron transfer between the cells and the electrode.19,20  Extracellular electron transfer manipulation (a microbial process) with chemical electron shuttles or electrode modifiers can be considered as a typical application of chemical bioengineering.

Regulation of cell physiology with chemical strategies is another interesting application of chemical bioengineering. Consequently, MES performance improvement was also achieved by cell physiology manipulation with chemical strategies. Cell permeability and cell adherence, which play important roles in the extracellular electron transfer and energy efficiency of MES, were successfully manipulated with the addition of surfactants or metal ions, or cell immobilization. In addition, quorum sensing signaling molecules that can coordinate the bacterial behaviors/physiology at the population level showed great promise on MES manipulation.21 

In this context, MES manipulation with chemical electron shuttles, electrode modifiers, surfactants, metal ions, cell immobilization, and quorum sensing will be summarized to illustrate chemical bioengineering in MES and will be described in this chapter.

Plant cell culture originating from Cell Totipotency Theory was proposed by Haberlandt, a German botanist, in 1902.22  Plant cell secondary metabolites are widely used, have significant economic value, and can be made into medicines such as paclitaxel, ginsenosides, and artemisinin. The structures of some secondary metabolites are too complex to be artificially synthesized at scale for practical purpose. For example, paclitaxel, a widely used anticancer drug, is obtained by semisynthesis by Baccatin III, isolated from the bark of the pacific yew, Taxus brevifolia. Because of environmental and resource factors, plant cell culture is a promising alternative technology for the mass production of valuable secondary metabolites. However, in general, the production of secondary metabolites in cell culture is too low, so some manipulative techniques are necessary to promote the productivity. Among these methods, chemical elicitations (by chemical elicitors) have been one of the best approaches for dramatically increasing secondary metabolite yields.23  The process is typical chemical biotechnology or bioengineering, in which some compounds are used to regulate a series of biological changes in cells or enzyme activity, which increases the production of secondary metabolites on a large scale.

Jasmonic acid (JA) and its methyl ester (MJA) are important members of the family of natural jasmonates. Exogenously adding MJA was shown to increase the production of secondary metabolites in a variety of plant species. Some synthetic elicitors have also been proven to be too. We describe a series of synthetic cell culture elicitors in Chapter 4, including MJA derivatives and benzothiadiazole (BTH) derivatives.24,25  Some of them display more potent activity in Taxus chinensis cell culture and Panax notoginseng cell culture than MJA, which reflects the full application of chemical bioengineering in plant cell culture.

Agrichemicals, including pesticides, fungicides, herbicides, and rodenticides, are very effective for crop protection. However, the excessive use of agrichemicals has caused some serious problems to the environment. The suffix “cide” means kill, so the action mechanisms of these kinds of plant protectors are to kill these pests, fungi and weeds, whilst not affecting the growth of plants. Therefore, the requirement for high selectivity, low toxicity, and low residues makes pesticides development difficult. The great biotechnology advantages from genetically modified (GM) crops haven’t been widely accepted due to some ethical problems and some potential concerns resulting from DNA recombination.

Like health products for people, some chemicals (plant activators) can be used to initiate systemic acquired resistance (SAR) to protect plants from a broad spectrum of diseases and pests by naturally influencing gene expression or adjusting some cascade changes including metabolism or pathogen-related (PR) protein expressions in plants, which is different from traditional pesticides or their metabolites acting directly on target insects, fungi and weeds. No antimicrobial activity in vitro either by the chemical itself or by its possible metabolites is the preliminary condition, so plant activators are called green plant protecting products. The process belongs to a kind of chemical biotechnology for special action mechanisms.

In Chapter 6, a systemic discussion of plant activators will be presented, including their history, action mechanisms, current situation, a few synthetic plant activators, and future developments.

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